Cocaine has recently been shown to be a potent hepatotoxin when administered to cytochrome P-450 induced mice. We have also observed that in many inbred strains of mice, cocaine is hepatotoxic with prior treatment with cytochrome P-450 inducers. In humans, there is some preliminary evidence to suggest that cocaine is hepatotoxic, at least when used with heroin. It has been found that cocaine must be biotransformed to initiate hepatic necrosis. However, neither the ultimate toxic metabolite nor the enzymes responsible for its formation have been determined. We have developed a noninduced mouse (DBA/2Ha) model which we will use to investigate cocaine-mediated hepatotoxicity. The enzymes involved in bioactivation of cocaine to its hepatotoxic intermediate will be determined by a series of in vivo experiments in which levels of drug metabolizing enzymes will be systematically altered and hepatotoxicity determined. Early events in cocaine mediated hepatotoxicity will be determined using a series of perfused liver experiments and by using an organ spectrophotometer in conjunction with the perfused liver. The role of glutathione in protection against cocaine mediated hepatotoxicity will be determined. The chemical reactivity of norcocaine nitroxide, the putative hepatotoxic cocaine metabolite, and some of its analogs will be investigated. Hepatocytes and microsomes will also be used to investigate the mechanism of hepatotoxicity mediated by cocaine and its metabolites, norcocaine and N-hydroxynorcocaine at the cellular and subcellular level. The lack of hepatic necrosis in non-induced ICR mice will be examined as it relates to this mechanism.